RORγt Program Overview
We are the leaders in discovering and developing orally active small molecule inhibitors of RORγt activity, for the treatment of a variety of autoimmune disorders, and have validated that inhibition of RORyt has clinical effect in psoriasis patients. Autoimmune disorders comprise a large number of diseases in which the body mounts an inappropriate immunological response against normal human tissues. These disorders include: psoriasis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease and multiple sclerosis, as well as other diseases. Due to the breadth of autoimmune disorders that a RORγt inhibitor may treat, we believe there is an opportunity to advance multiple compounds into clinical development. We have two orally active, once-a-day product candidates in development, our most advanced in the clinic, VTP-43742, and our second product candidate, VTP-45489, which is expected to enter the clinic in the third quarter of 2016.
In March 2016, we announced positive top-line clinical and biomarker results from the Phase 2a proof-of-concept multiple ascending dose trial in patients with moderate to severe psoriasis, in which VTP-43742 was administered once daily for four weeks. In the trial, clear signals of efficacy were observed in the 350 mg dose group and in the 700 mg dose group. Between weeks zero and two, there was a modest onset of PASI reduction, and for the last two weeks of the trial, and particularly between weeks three and four, there was an acceleration of the rate of reduction in PASI score in both the 350 mg and 700 mg dose groups, suggesting the potential for greater reductions in PASI scores with longer duration of treatment. Full efficacy in psoriasis is not generally seen in other classes of drugs until at least 12 weeks of continuous therapy. We believe the PASI score reductions observed for VTP-43742 at four weeks and the acceleration of rate of PASI reduction between weeks three and four are consistent with the potential of VTP-43742 to achieve greater levels of efficacy with extended treatment. VTP-43742 was shown to be generally well tolerated at all dose levels tested, with no serious adverse events reported. In the 700 mg dose group, reversible transaminase elevations greater than three times the upper limits of normal were observed in three patients while being dosed, which did not trigger any stopping rules of the trial, and two patients reached those levels after the four weeks of dosing completed. The transaminase levels fully reversed for all of these patients and none of them experienced related elevations in bilirubin, had any other sign of serious liver damage or required any further action. Drug-related elevated transaminase levels were not previously observed in our preclinical or clinical trials. Pharmacokinetics were consistent with once-a-day dosing.
Biomarker data were assessed in both the 350 mg and 700 mg dose groups. Two common inflammatory cytokines found in psoriasis patients were assessed in the Phase 2a proof-of-concept trial, plasma IL-17A and IL-17F, as well as skin IL-17A and IL-17F. There was a dose dependent reduction in plasma IL-17A and IL-17F from baseline. All plasma IL-17 A and IL-17F reductions were statistically significant. Skin IL-17A and IL-17F changes were also measured in both the 350 mg and 700 mg dose groups. The skin IL-17A changes in both the 350 mg and 700 mg dose groups were mixed with no clear change and changes in skin IL-17F were statistically significant for both dose groups compared to baseline. The skin biomarker results are consistent with the results of systemic monoclonal antibodies targeting the TH17 pathway in patients with psoriasis.
We plan to initiate a 16-week Phase 2 clinical trial in psoriasis patients in the fourth quarter of 2016 with three objectives: (1) assess the 16 week efficacy of VTP-43742 in moderate to severe psoriasis patients; (2) assess the safety and tolerability of the product candidate in a larger population and over a longer treatment period; and (3) position VTP-43742 to begin pivotal trials as soon as practicable after the completion of the Phase 2 clinical trial, if successful. We continue to assess whether clinical trials in additional indications are appropriate for VTP-43742. Top-line data from the Phase 2 clinical trial is expected to be announced in the second half of 2017.
These data build upon the previously announced September 2015 positive top-line results from a single ascending dose trial that assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of VTP-43742 in 53 healthy human volunteers over several dose levels. In November 2015, we announced positive top line results from a Phase 1 multiple ascending dose clinical trial of VTP-43742 designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of multiple ascending doses of VTP-43742 in up to 40 healthy human volunteers over multiple dose levels.
We have clinically validated RORγt as a therapeutic target, providing us the confidence to continue to advance a second RORγt clinical candidate, VTP-45489, in our pipeline. VTP-45489 is a chemically distinct compound from VTP-43742. We believe VTP-45489 has a competitive pre-clinical profile and is expected to be dosed once-a-day, making it a desirable clinical candidate. We plan to initiate a single ascending dose trial in healthy human volunteers assessing safety, tolerability, pharmacokinetics and pharmacodynamics across a broad dose range. The trial is expected to initiate in the third quarter of 2016.
About Autoimmune Diseases
Autoimmune diseases, where the immune system attacks normal tissue, make up a large number of human disorders including psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis and inflammatory bowel disease, as well as other autoimmune disorders. Psoriasis, a chronic autoimmune disorder of the skin, affects an estimated 7.5 million Americans.
Increased activity of a class of lymphocytes called Th17 cells and excess production of pro-inflammatory proteins, including Interleukin 17, or IL 17, by these cells are critical parts of the pathophysiology of many human autoimmune disorders. RORγt is a nuclear hormone receptor that is essential for the formation and function of Th17 cells.
Vitae Pharmaceuticals believes inhibition of RORγt activity in Th17 cells will be beneficial for the treatment of multiple autoimmune disorders, specifically, psoriasis, psoriatic arthritis, ankylosing spondylitis, RA, IBD and other autoimmune disorders.
Currently available autoimmune disease drugs, specifically for the treatment of psoriasis, include topical steroids, phototherapy or light therapy, systemic agents, and biologics. Vitae Pharmaceuticals anticipates VTP-43742 will be the most effective oral therapy used for the treatment of moderate to severe psoriasis.
Vitae Pharmaceuticals is advancing its wholly-owned autoimmune disease drug candidates, VTP-43742 and VTP-45489, through clinical trials.